The proposed work is devoted to studies of the regulation of endosteal bone volume. Such studies are essential to our overall long-term goal, which is to cure and prevent osteoporosis. Our position is that in osteoporosis, endosteal bone volume is lost, that faulty endosteal bone volume regulation accounts for this bone loss, and that this defect may involve our putative coupling factor. Studies of the effects of calcium regulating hormones at the endosteum led to the concept that the coupled increase in formation subsequent to an increase in resorption was an endosteal counter-regulatory measure mediated by a coupling factor and functioning to maintain endosteal bone volume in opposition to calcium regulating hormones. We will test our hypothesis, by means of in vitro studies, that during bone resorption a coupling factor is liberated either from bone matrix or from endosteal bone cells. The factor(s) will then be purified; its secretion, specificity and action will be studied. In addition, we will study the regulatory interactions among the four bone cell populations (committed and mature osteoblasts and osteoclasts) in response to a perturbation of only one of these cell populations. The latter will include studies of the ia rat in which the activity of the osteoclast population is probably exclusively impaired, and studies of treatment with cis-hydroxyproline, an agent that may exclusively inhibit the activity of the osteoblast population. For these studies we will develop a tritiated thymidine kinetic method to measure cell production rates of osteoblasts and osteoclasts which will be measures of the committed osteoblast and committed osteoclast populations respectively. This method also will be applied to the studies of the W/Wv mouse which has a stem cell defect and which may provide a means to determine if the coupling of osteoblast number to osteoclast number, a finding which we have documented, operates at the stem cell level.